ABSTRACT ? Research Pilot Breast cancer is the most frequent malignancy in women worldwide, yet there are pronounced differences in incidence and mortality between racial/ethnic groups. Hispanics/Latinas (H/L) are a growing and understudied group characterized by a variable admixture of European, Indigenous American, and African ancestry. Breast cancer is genetically and biologically heterogeneous, consisting of multiple molecular subtypes which differ in terms of prognosis and response to treatment. The PAM50 gene expression panel distinguishes five main intrinsic subtypes of breast cancer: Luminal A, Luminal B (both ER?-positive), Her2/Neu enriched, Basal-like and Normal-like. The Luminal B subtype has a poorer prognosis than Luminal A, lower expression of nuclear hormone receptors, and higher expression of proliferation markers. These tumors benefit less from endocrine therapy, and remain the largest cause of breast cancer mortality. In a cohort of 301 clinically annotated H/L breast cancer patients, we found that among mixed-ancestry Hispanic/Latina patients, the frequency of Luminal B tumors is remarkably high (>42%). Among these H/L patients, Luminal B tumors are characterized by a more aggressive clinical presentation than Luminal A tumors, suggesting that the high frequency of Luminal B tumors is associated with a strong health outcomes disparity. A higher incidence of Luminal B tumors has been reported among US H/L patients, but the number of H/L in the study was too small to draw definite conclusions. Using RNASeq, we found that H/L Luminal B tumors are frequently characterized by increased expression of the ERBB2 (Her2/Neu) receptor, the GRB7 adaptor and the migration and invasion enhancer, MIEN1. Expression of these three genes was linked to Indigenous American (IA) ancestry and all are located at Ch17q12. ERBB2 and GRB7 are co-amplified in Her2/Neu enriched tumors, and are correlated with endocrine resistance and poor prognosis in ER?-positive tumors. A link between genetic ancestry and Luminal B breast cancer can help identify prognostic biomarkers as well as molecular features for specific therapeutic approaches (precision medicine) in H/L. Our primary hypothesis is that H/L ethnicity/IA ancestry are associated with a high incidence of Luminal B tumors and with increased expression of ERBB2, GRB7 and MIEN1. Furthermore, we propose that the elevated expression of these three genes may be the consequence of altered promoter or enhancer methylation linked to IA ancestry. To test these ideas, we will examine a novel cohort of H/L breast cancer patients in two specific aims: (1) to determine the molecular portraits of PAM50- confirmed Luminal B tumors from H/L breast cancer patients utilizing RNASeq, and to correlate these findings with clinicopathological parameters and outcomes, and (2) to establish the relationship of ERBB2, GRB7 and MIEN1 with promoter methylation, ancestry, clinicopathological parameters and clinical outcomes.